2025-08-06 静岡県立大学,生命創成探究センター,分子科学研究所
<関連情報>
- https://www.u-shizuoka-ken.ac.jp/news/20250806/
- https://www.u-shizuoka-ken.ac.jp/media/20250806_press.pdf
- https://pubs.acs.org/doi/10.1021/jacs.5c06850
酵素的プレニル化による抗菌ペプチドの化学空間拡張 Expanding the Chemical Space of Antimicrobial Peptides via Enzymatic Prenylation
Hikari Ozawa,Azusa Miyata,Seiichiro Hayashi,Noriyuki Miyoshi,Koichi Kato,Sohei Ito,and Daisuke Fujinami
Journal of the American Chemical Society Published: July 13, 2025
DOI:https://doi.org/10.1021/jacs.5c06850
Abstract
Antimicrobial peptides act primarily at the bacterial membrane interface. We report a biocatalytic strategy that enhances their potency by up to 18-fold. The improvement results from the enzymatic installation of bulky isoprenoid chains, which strengthens peptide–membrane interactions and promotes membrane destabilization. We characterize PalQ, an isoprenoid synthase-related prenyltransferase that is uniquely amenable to enzyme engineering. PalQ catalyzes prenylation at both N- and C-terminal tryptophan residues via positionally distinct Cδ2 and Cγ alkylation, respectively. Structure-guided mutagenesis of the prenyl donor pocket, combined with glycine substitutions near the acceptor tryptophan, expanded PalQ’s substrate scope to include diverse antimicrobial peptides and long-chain donors such as geranylgeranyl diphosphate. A computationally optimized PalQ variant further improved performance under high-salt and organic solvent conditions, enabling late-stage modification of poorly soluble peptides. These results establish PalQ as a versatile platform for site-selective lipidation and expand the accessible chemical space for peptide and protein engineering.
